Neurocognitive change in the era of HIV combination antiretroviral therapy: A CHARTER Study

1. CNS HIV Anti-Retroviral Therapy Effects Research Neurocognitive change in the era of HIV combination antiretroviral therapy: A CHARTER Study RK Heaton, Ph.D., DR Franklin, Jr., B.S., R Deutsch, Ph.D., SL Letendre, M.D.,RJ Ellis, M.D., Ph.D., K Casaletto, M.S., MJ Marquine, Ph.D., SP Woods, Psy.D., F Vaida, Ph.D., JH Atkinson, M.D., TD Marcotte, Ph.D., JA McCutchan, M.D.,AC Collier, M.D.,CM Marra, M.D., DB Clifford, M.D., BB Gelman, M.D., Ph.D., JC McArthur, M.B.B.S., S Morgello, M.D., DM Simpson, M.D., I Abramson, Ph.D.,A Gamst, Ph.D., C Fennema-Notestine, Ph.D., DM Smith, M.D., and I Grant, M.D.for the CHARTER Group Supported by NIMH and NINDS | N01 MH22005 / HHSN271201000036C / HHSN271201000030C

3. Background • HIV-associated neurocognitive disorders (HAND) common (30% - 50%) despite effective cART • Common source of disability; amplified other disabilities by hampering compensatory strategies and treatment adherence • HAND diagnoses can evolve - variable clinical trajectories • Most longitudinal studies limited follow-up duration (6-12 months) or in the context of clinical trial

4. Objective • Evaluate predictors of neurocognitive change over long-term follow-up in PLWHA • Long-term goal: identify interventions to prevent decline and enhance improvement

5. CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) • HIV+ participants from 6 sites followed longitudinally • Johns Hopkins University (PI: Justin McArthur) • Mount Sinai School of Medicine (PI: Susan Morgello, David Simpson) • University of California San Diego (PI: J. Allen McCutchan) • University of Texas Medical Branch (PI: Benjamin Gelman) • University of Washington Seattle (PI: Ann Collier, Christina Marra) • Washington University, St. Louis (PI: David Clifford)

6. 15 tests assessing 7 domains Verbal Fluency Speed of Information Proc. Attention/Working Memory Motor Abstraction/Executive Learning Memory (delayed recall) Overall performance summarized as a global deficit score (GDS) CHARTER NeurocognitiveBattery

7. Primary Outcome: Reliable NP Change • Multivariate regressions predicting FU scores • Observed – Predicted FU scores/ SD residual = z=score • Average Z-scores on battery = sRCS • Use 90% CI for sRCS to classify changes in individuals over time • Separately, used results of these cohorts (median test-retest differences) to correct for practice effect in classifying impairment at follow-up visits

8. Potential Predictors Evaluated General Medical Health Indicators • hematocrit, serum albumin, total protein, LFTs Indicators of HIV disease and treatment success • cART status: on vs off (naïve + discontinued) • initial and follow-up plasma viral loads, CD4 Comorbid Conditions • Neurocognitive comorbidities (head trauma, etc) • Minimal, moderate, severe (Frascati) • Past substance abuse/dependence (e.g., methamphetamine) • Mood disorders - depression (Beck)

9. Cox Regression Analysis • Time to NC decline • Time to NC improvement • Univariable predictors with p < .10 eligible for inclusion multivariable model • Selected variables combined into a Cox time-dependent multivariable model • backward elimination with minimal Akaike Information Criterion (AIC) to reduce

10. Baseline Demographics * Sources of impairment other than HIV

11. HIV Disease and Treatment Indicators

12. NP Change Status in CHARTER Sample with ≥ 4 visits (n=436)

13. Sustained viremia associated with neurocognitive decline p= .005

14. Significant Multivariable Time-Dependent Predictors of Time to Neurocognitive Decline Multivariable Cox Regression Model p <0.0001

15. Multivariable Cox Regression Model with Time-Dependent Predictors to Estimate Time to Neurocognitive Improvement Multivariable Cox Regression Model p <0.0001

16. Summary In this broadly representative sample of PLWHA in the U.S., most with extensive ARV-exposure: • Over median 3 years follow-up, 22.7% declined, 16.5% improved neurocognitively • Predictors of earlier neurocognitive decline: off cART, poor general medical health indicators (albumin, hematocrit), severe neurocognitive comorbidity (not HAND eligible), neuropsychiatric comorbidity (past substance use, ongoing depression) • Predictors of earlier neurocognitive improvement: greater cognitive reserve (pre-morbid IQ), good general medical health indicators (serum protein, AST), absence of lifetime major depressive disorder

17. Conclusions and Future Directions • Enhancing neurocognitive function in PLWHA needs attention not only to optimizing cART, but also to comorbidities, particularly substance use and depression, as well as general medical health • Future studies should be designed to assess the impact of treatment of comorbid neuropsychiatric disorders with respect to improved antiretroviral adherence, with positive feedback on overall health • Unexplained variance in long-term NC change: develop surrogate biomarkers (e.g., imaging) of improvement that might be used to accelerate testing of new treatments

18. CHARTER Sites David Clifford Justin McArthur Ann Collier Christina Marra Susan Morgello David Simpson Ben Gelman National Institutes of Health Mental Health Neurological Disorders and Stroke Acknowledgements Thanks to all our Study Volunteers And to Collaborating Investigators and Sponsors CHARTER Coordinating Center • Igor Grant • Ron Ellis • Scott Letendre • Robert Heaton • Thomas Marcotte • Christine Fennema-Notesine • David Smith • Florin Vaida • J Allen McCutchan • J Hampton Atkinson

19. Study Comparison

20. Backup Slides

21. Global Mean T at Baseline and Last Visit by NP Change Status Last Visit: Decline > Stable, Improve Baseline: No Differences

22. Time Dependent Univariable Predictors of Earlier NC Improvement (Survival Analysis*) * Univariable predictors with p < .10 chosen for inclusion multivariable model